The invention is related to thrombus dissolution and thrombolysis. In particular it is related to the use of lasers and pharmaceutical agents to dissolve an occlusive thrombus in a blood vessel by inducing vasodilation in the vicinity of the thrombus.
Four approaches are currently available or under development for the treatment of stroke, myocardial infarction, and other vascular occlusive disorders: (1) the use of high-intensity pulsed lasers to disrupt a thrombus or embolus by either ablation or photoacoustic shock; (2) catheterization, angioplasty, and stent emplacement to physically rupture a thrombus or enlarge the vascular lumen adjacent to an atheroma; (3) the administration of thrombolytic or dethrombosing agents to chemically dissociate a thrombus, often followed by administration of platelet inhibitors (also known as antiplatelet agents) to prevent rethrombosis; and (4) thrombectomy, in which a thrombus or atheroma is mechanically minced and removed. Each of these methods is associated with potential harmful effects or poor efficacy in some circumstances.
High peak intensity, high energy fluence pulsed-wave lasers are capable of ablating or dissolving thrombi as a result of the transduction of laser light into acoustical, mechanical, chemical, or thermal energy (Topaz, 1996, 1998). In addition to chemical degradation caused by the absorption of laser light in the ultraviolet (UV), visible, or infrared wavelengths, the ablation technique creates tiny gas bubbles within the thrombus which aid in its disruption. In the photoacoustic approach, the thrombus is destroyed by shock waves transmitted to it via a cavitation bubble which forms at the tip of the catheter that delivers the laser beam. While these methods can be effective, they carry several risks. The high pressure which builds up inside an irradiated thrombus can cause it to fragment, producing distal emboli that pose a significant danger to the patient in the form of secondary occlusions or strokes. If such high-power laser pulses (energy fluence of 300 mJ/mm2) are misdirected toward the vessel wall, they can produce intense shock waves resulting in permanent tissue damage, acute vessel closure, and dissections and perforations of the vessel (Topaz 1996, 1998). These are potentially life-threatening side effects which are not infrequent. For example, the arterial dissection rate is 13-17% in patients treated with pulsed-wave lasers (Topaz 1994; Litvack et al., 1994). A recent improvement in this approach was presented by Buckley et al. (1999), who used a 577 nm pulsed dye laser with an energy fluence of 10 mJ/mm2 to debulk colored (red) thrombi; white thrombi, composed of aggregated platelets or platelets and fibrin, are unlikely to be affected by this treatment.
Balloon angioplasty is generally successful in restoring patency of an artery occluded by atheromatous tissue, but the results are often suboptimal with a large atheroma. Furthermore, because of the tendency for regrowth of atheromatous tissue at the site of injury resulting from an angioplasty procedure, the rate of restenosis is typically 50-60% within six months. Laser angioplasty, in which an atheroma is ablated by direct high-intensity irradiation, has a similar restenosis rate. Laser angioplasty also carries the risk of damage to the vessel wall from heat generated within the irradiated atherosclerotic plaque.
Tissue plasminogen activator (t-PA) therapy is considered beneficial for acute myocardial infarction and stroke. Fibrin-rich red thrombi are lysable by thrombolytic agents such as t-PA and urokinase, as are white platelet-fibrin thrombi, which structurally resemble those observed in the clinic after plaque rupture (Davies and Thomas, 1985; Fernandez-Ortiz et al., 1994). In contrast, occlusive fibrin-free white thrombi, consisting solely of aggregated platelets cross-linked by GPIIb-IIIa receptor-mediated fibrinogen bridges, are resistant to lysis by t-PA. Thrombolytic drugs achieve vessel patency in only 75% of cases of acute myocardial infarction (Topaz, 1996), and considerably less in the case of stroke (del Zoppo, 1992). Thrombolytic drugs are associated with an elevated bleeding risk and sometimes leave a residual narrowing at the site of the thrombus. Another area of pharmacological intervention is the use of platelet inhibitors (antiplatelet agents). The prevention of refractory platelet thrombi is of much commercial interest. A major effort is underway to develop RGD (arginine-glycine-aspartic acid) antagonists which inhibit platelet binding mediated by intraplatelet fibrinogen bridges between GPIIb-IIIa membrane receptors (Mousa et al., 1994). These drugs are intended to mitigate residual thrombogenicity of the vascular wall, which often results from incomplete removal of the thrombus following treatment with thrombolytic agents such as t-PA.
Also under commercial development are dethrombosing agents, intended especially for use on thrombi with a high platelet content. These can be natural enzymes such as hirudin from the medicinal leech, the synthetic compound argatroban, and many similar drugs. All of these substances inhibit thrombin, an enzyme required for stabilization of platelet aggregates. If thrombin activity in a thrombus can be inhibited, dethrombosis (release of individual platelets) and subsequent dissolution of the thrombus may result (Wysokinski et al, 1996)
There is a need in the art for additional means for disrupting thrombi so that thrombi resistant to current techniques or whose removal entails undesirable side effects can be treated successfully.
It is an object of the invention to provide methods for dissolving a thrombus in a blood vessel of a mammal. This and other objects of the invention are provided by one or more of the embodiments described below.
One embodiment of the invention provides a method for dissolving a thrombus in a blood vessel of a mammal. An ultraviolet (UV) laser beam is directed onto the internal or external surface of the blood vessel. The laser beam is directed onto the vessel wall within about 10 vessel diameters of the thrombus, but does not impinge on the thrombus. Subsequent to illuminating the vessel with the laser beam, the thrombus dissolves.
Another embodiment provides another method for dissolving a thrombus in a blood vessel of a mammal. A pharmacological agent which aids in thrombus dissolution is administered to the mammal, and a UV laser beam with an is directed onto blood vessel. The laser beam is directed onto the vessel wall within about 10 vessel diameters of the thrombus, but does not impinge on the thrombus. Either a direct beam or a beam transmitted through an optical fiber can be used. Subsequent to illuminating the vessel with the laser beam, the thrombus dissolves.
Yet another embodiment provides another method for dissolving a thrombus in a blood vessel of a mammal. A UV laser beam is directed onto the thrombus using an optical fiber or liquid core optical guide. In this method, the laser beam does not ablate or photoacoustically shock the thrombus. Subsequent to illuminating the thrombus, the thrombus dissolves.
These and other embodiments of the invention provide the art with new techniques for treating diseases associated with blood vessel occlusive thrombi.